Immunoglobulin A1 (IgA1) deposition in human tissues and organs is a characteristic of several human diseases which include, but are not limited to, IgA nephropathy, dermatitis herpetiformis (DH), and Henoch-Schoenlein purpura (HSP). The IgA1 deposits are responsible for a variety of clinical manifestations such as renal failure, skin blistering, rash, arthritis, gastrointestinal bleeding and abdominal pain.
There are several available treatment options for patients that present with abnormal IgA1 deposition. These include administration of corticosteroids that have immunosuppressive and anti-inflammatory properties, dietary fish oil supplements that reduce renal inflammation, angiotensin converting enzyme inhibitors that reduce the risk of progressive renal disease and renal failure, and dapsone, a drug used to treat DH. DH can also be treated by gluten-free diet, as this disorder often is accompanied by gluten sensitive enteropathy. Such treatments do not directly act on IgA1 deposits in tissue or organs.
Human immunoglobulin A (IgA) synthesis exceeds the combined total of all the other immunoglobulin classes (Rifai et al. J. Exp. Med. 191:12, Jun. 19, 2000 2171-2181). It is estimated that 66 mg of IgA/kg of body weight is produced every day, compared with 34 mg of IgG and 7.9 mg of IgM. There are two isotypes of IgA, IgA1 and IgA2. On mucosal surfaces (gut, respiratory tract, genital track, etc) both IgA1 and IgA2 are present, synthesized by local B cells. In the blood, however, IgA1 predominates, and its origin is B cells in the bone marrow, lymph nodes, and spleen (James V. Donadio, M. D., and Joseph P. Grande, M. D., PHD. N Engl J Med, Vol. 347, No. 10: 738-748. Sep. 5, 2002).
The main differences between the IgA1 and IgA2 isotypes lie in the hinge region of the heavy polypeptide chain; a 13-amino acid deletion characterizes the IgA2 hinge region. This segment in IgA1 contains several Ser and Thr amino acid residues that are O-glycosylated, but the absence of this segment in IgA2 results in IgA2 having no O-linked oligosaccharides. IgA1 also has two N-linked carbohydrates in the CH2 domain at residue Asn263, and in the CH3 domain at Asn459. All IgA2 allotypes have two additional N-linked sites, in the CH1 domain at Asn166 and in the CH2 domain at Asn337. The IgA2m(2) and the IgA2(n) allotypes have a fifth N-linked site in the CH1 domain, at Asn211. N-linked glycans are complex structures attached to specific asparagine residues and are common on circulating proteins. In contrast, O-glycans as in the IgA1 hinge consist of simple sugar chains connected to serine or threonine residues, and while abundant on all-surface proteins, they are uncommon on circulating proteins. In IgA1 each O-glycan has a core N-acetyl galactosamine (GalNAc) unit in O-linkage with serine or threonine, and the chain may be extended by the sequential addition of galactose (Gal) in β1,3 linkage with GalNAc, and with one or two sialic units in 2,3 linkage with Gal or 2,6 linkage with GalNAc (Alice C. Allen et al. J Am Soc Nephrol 10: 1763-1771, 1999; Taj S. Mattu et al., J. Bio. Chem. 1998, 273:4:2260-72). Thus, each O-glycan may consist of one of four different forms. These O-glycans are identical to those displayed by membrane-bound proteins such as mucins.
Several recent studies have implicated O-glycosylation defects in IgA1 as being involved in the pathogenesis of IgA deposition diseases (Alice Allen et al., J Am Soc Nephrol 10: 1763-1771, 1999; Mestecky J, Tomana et al., Contrib Nephrol 1993; 104:172-82; Milan Tomana et al., The J Clin Invest, July 1999, Volume 104, Number 1, 73-81; Tomana M, Matousovic et al., Kidney Int 1997; 52:509-16; Allen A C et al., Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. Kidney (Abstract) Int 2001; 60:969-73.
As indicated earlier, it has been proposed that the lack of galactose residue could substantially reduce serum IgA1 clearance; that is, it keeps this form of IgA in the circulation for a longer time than normal. The mechanism behind failure of IgA1 proteins to acquire normal amounts and form of O-linked glycans are unknown.